Liver fibrosis is a chronic disease in which the damaged parenchymal tissue fails to regenerate. This damage causes liver stellate cells to be over active and triggers the extra cellular matrix (ECM) synthesis to increase. Advanced liver fibrosis can result in cirrhosis and life-threatening live failure. Cirrhosis is a disease of the liver with as a pathological hallmark the development of scar tissue that replaces normal parenchyma. Damage to these hepatic parenchyma (due to inflammation) leads to activation of the stellate cell, which increases fibrosis through production of myofibroblasts. This process might result in the generation of fibrous tissue bands (septa), which eventually replace the entire liver architecture ending in the obstruction of blood flow.
Recently, it has become clear that 5-HT2B might play a role in the progression of liver fibrosis and/or cirrhosis. M. Ebrahimkhani et al have shown that selective antagonism of 5-HT2B enhanced hepatocyte growth in models of acute and chronic liver injury (Nature Medicine 17, 1668-1673 (2011)).
5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT).
There is a need for selective and potent 5-HT2B antagonist chemical classes, useful in the treatment or prevention of fibrosis and/or cirrhosis.
Amongst the problems which 5-HT2B antagonists may encounter are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, low solubility and difficulty of synthesis.
There is a need for drugs to treat liver fibrosis and/or cirrhosis, more specifically 5-HT2B antagonists that may overcome at least one of these disadvantages or that have additional advantages such as increased potency or an increased safety window.
WO2013/006394, published on Jan. 10, 2013, relates to a subclass of sulphamoyl-arylamides active against Hepatitis B Virus (HBV). WO2013/096744, published on Jun. 26, 2013 also relates to sulphamoyl-arylamides active against HBV.